tbuckley/cabot-search huggingface dataset:
Abstract 4232: TLR2 agonist as a novel therapeutic approach to treat pancreatic adenocarcinoma
Authors: Arpit Dheeraj, Chandreshwar Shukla, Dhanir Tailor, Nayan K. Jain, Kirsten Stefan, Chintan D. Patel, Rajiv Modi, Bakulesh M. Khamar, Sanjay V. Malhotra
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with an overall 5-year survival rate of &amp;lt;10% due to late stage diagnosis and poor clinical outcome with existing therapies. PDAC displays a high degree of tumor heterogeneity and immunosuppressive tumor microenvironment with lower tumor infiltrating lymphocytes (TIL). These factors contribute to resistance against chemotherapies and immunotherapies. Immunotherapies have shown activities across different tumor types including chemotherapy or targeted therapy resistant cancers however these options have little efficacy in the PDAC tumor. Here, in this study we tested the efficacy of gemcitabine in combination with Cadi-05 (TLR2 agonist) against established murine PDAC tumor models (Pan02 in C57/BL6 and 688M in B6129SF1/J). Animals were randomized to receive gemcitabine, Cadi-05, their combination or no treatment when they had tumor size ≈ 50 mm3, 65mm3 and 100 mm3. The weekly treatment of gemcitabine, Cadi-05 and their combination inhibited the tumor progression across all tumor sizes. At the end of study, PBMC and tumors were collected and analyzed for different immune parameters. Results revealed that Cadi-05 treatment alone was associated with increase in CD4+ and CD8+ T cells in PBMC as well as amongst TIL with significant decrease in their expression of immunosuppressive markers like FOXP3 and PD-1. Its combination with gemcitabine synergized the effect of each other. There was further increase in absolute TIL as well as TIL expressing CD4+ and CD8+ markers with decrease in FOXP3 and PD-1 expressing CD4+ and CD8+ TIL. Inhibition of tumor progression was associated with improved effector function of PBMC. Synergy between Cadi-05 and gemcitabine was also evident in effector function. In presence of established tumor, TLR2 agonist Cadi-05 improves effector function, increases CD4+ and CD8+ expressing TIL, decreases immune suppressive TIL and retards tumor growth. Our study suggests that combination of gemcitabine and Cadi-05 inhibits the tumor growth irrespective of its size and it is coupled with increased anti-tumor response and decreased immunosuppressive function Citation Format: Arpit Dheeraj, Chandreshwar Shukla, Dhanir Tailor, Nayan K. Jain, Kirsten Stefan, Chintan D. Patel, Rajiv Modi, Bakulesh M. Khamar, Sanjay V. Malhotra. TLR2 agonist as a novel therapeutic approach to treat pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4232.
Abstract 2885: Generation of TCR-like fully human antibodies against HLA-antigen-peptide complexes using HLA transgenic RenMice
Authors: Jun Du, Nannan Wang, Li Hui, Ruixue Wang, Taolin Liu, Qingcong Lin
Journal: Cancer Research (2022)

Abstract With the development of immunotherapy in recent years, therapeutic antibodies have become a major player combating cancer with the limitation of recognizing cell surface or secreted molecules. In contrast, the human T cell receptor (TCR) recognizes its cognate peptide antigen when presented on human leukocyte antigen (HLA) molecules, and thus detects a broader range of targets including intracellular proteins. Here we established an innovative strategy of generating fully human TCR mimic (TCRm) antibodies that can recognize antigen with a higher specificity and affinity. Previously, Biocytogen established RenMab™ and Renlite࣪ mice (RenMice). These humanized immunoglobulin mouse models generate fully human antibodies that carry human Ig heavy chain and human kappa light chain variable domains. Here, HLA genes were introduced into RenMice to build tolerance towards HLA. When immunized with HLA- peptide complexes, these mice generate antibodies that specifically target the HLA-Peptide complex, with no reactivity to HLA alone nor other peptide-HLA complexes. Compared to natural TCRs, these TCRm antibodies show higher affinity and specificity. Using optimized immunization methods and high-throughput screening, our antibody discovery platform generated fully human TCRm antibodies from HLA/RenMab™ and HLA/Renlite™ mice. Producing TCR-like binders with this unique TCRm technology can become a very powerful tool in the immunotherapy field. Citation Format: Jun Du, Nannan Wang, Li Hui, Ruixue Wang, Taolin Liu, Qingcong Lin. Generation of TCR-like fully human antibodies against HLA-antigen-peptide complexes using HLA transgenic RenMice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2885.
Abstract 2791: Integrating biospecimen science approaches into clinical assay development-PAR 22-049
Authors: Lokesh Agrawal, Abhi Rao, Ping Guan, Miguel Ossandon, Helen Moore
Journal: Cancer Research (2022)

Abstract Introduction to the problem: Biospecimens are the essential starting materials for the biomarker assays that enable precision medicine. Biospecimen preanalytical factors can directly influence molecular results from assays conducted for basic research, biomarker discovery, and biomarker validation, and can also influence the development of validated clinical assays. The U.S. National Cancer Institute (NCI) Biorepositories and Biospecimen Research Branch supports extramural research as a part of this FOA to investigate and mitigate preanalytical challenges facing clinical assay development and analytical validation in a variety of biospecimen types. The overall goal of this initiative is to expedite biomarker clinical assay development through evidence based standardization of biospecimen handling practices. The work is centered on emerging and clinically relevant biomarker assays conducted on a variety of molecular platforms. Proposed solution and methods: Researchers may investigate tissue and fluid biospecimens including core biopsies, fine needle aspirates, tissue exudates, blood, urine, saliva, breast milk, feces, sweat, CSF, and pleural and esophageal aspirates. Investigator designed experiments explore how different biospecimen preanalytical conditions affect biomarkers in a clinical setting. To date, ten grants have been funded. The grants address important areas in biospecimen science in both liquid and solid biopsy biopsies in breast cancer, glioblastomas, lung cancer, bladder cancer, prostate cancer, cutaneous and peripheral T cell lymphoma. Investigators can collaborate with each other and with the NCI, FDA and NIST through the U01 funding mechanism. Conclusions: The results from this research program will elucidate how analytical quantification of clinically relevant biomarkers is affected by patient context factors, variation in biospecimen collection, processing, and storage procedures, and how such effects can be mitigated to improve the development, performance and accuracy of clinical biomarker assays utilized in clinical research and patient care. The receipt dates for this program, PAR 22 049 in 2022, are January 11, 2022, June 7th, 2022, and September 13th, 2022. Citation Format: Lokesh Agrawal, Abhi Rao, Ping Guan, Miguel Ossandon, Helen Moore. Integrating biospecimen science approaches into clinical assay development-PAR 22-049 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2791.
Abstract 5606: GlycoConnect™ immune cell engagers (GC™-ICEs). A non-genetic approach to targeted IL-15 immunotherapy
Authors: Remon van Geel, Floris van Delft
Journal: Cancer Research (2022)

Abstract Engagement of T cell or NK cells to harness a patient’s immune system is a promising approach in immuno-oncology. An immunocytokine, i.e. a tumor-targeting antibody (fragment) genetically fused to an immunostimulatory cytokine, is specifically designed for this purpose. Fusion antibody-IL-15 immunocytokines, based on a variety of molecular architectures, are currently finding their way to the clinic with promising results. Here we demonstrate how GlycoConnect™, a site-specific conjugation technology anchoring on the native antibody glycan, can be applied for attachment of IL-15 without prior antibody engineering. The molecular architecture of the resulting immune cell engagers (ICEs) can be readily tailored to 2:2 or 2:1 ratio (anti-TAA:IL-15) to mitigate cytokine release syndrome. Moreover, we show how immunostimulatory activity can be regulated via linker design, either by tailoring of IL-15-antibody spacing or by generation of a conditionally active IL-15 format. Structural and functional studies will be presented to corroborate the architecture of these GC™-ICEs and in vitro and in vivo activity in a syngeneic mouse model. Citation Format: Remon van Geel, Floris van Delft. GlycoConnect™ immune cell engagers (GC™-ICEs). A non-genetic approach to targeted IL-15 immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5606.
Abstract 2495: Clinical and demographic predictors of survival for fibrolamellar hepatocellular carcinoma patients - A patient-community registry-based study
Authors: Amichai Berkovitz, Rachael D. Migler, Adam Qureshi, Roger Vaughan, Erin L. Marcotte, Sanford M. Simon
Journal: Cancer Research (2022)

Abstract Fibrolamellar Carcinoma (FLC), a rare liver cancer, has yet no specific tools to evaluate its prognosis. This study aims, in partnership with the patient community, to search for associations between various demographic and clinical factors and overall survival of patients, to assess prognostic factors. We performed a retrospective analysis on a community-based patient registry (The Fibrolamellar Registry http://fibroregistry.org) to examine relations between survival and different variables. The variables examined were demographic (gender), clinical (age at diagnosis, tumor size, number of tumors inside the liver, presence of positive lymph nodes or distant metastasis) as well as treatment modalities (surgery or systemic therapy). Kaplan-Meier survival plots were created for the overall research population and for stratifying by unadjusted variables. Cox proportional hazards model was used for multivariable analysis of hazard ratio (HR) for death at any time among groups, adjusting for variables found significant in the univariate analysis. Among 150 patients, (89 females and 61 males), median overall survival time from diagnosis to death or loss of follow-up was 8 years and 2 months. Features with independent positive effect on survival were female gender, as well as being treated with surgery alone. In contrast, having 10 or more tumors inside the liver had a negative effect on survival. Positive lymph nodes at diagnosis, and distant metastasis at diagnosis, were both associated with poorer prognosis, though did not remain independent when adjusting for covariables. We could not find an effect of age at diagnosis or tumor size at its largest measurement, on survival. In conclusion, our study suggests gender is a significant prognostic factor for FLC patients, with females having a better outcome than males. Surgical removal of the tumor, without additional systemic therapy is a positive prognostic factor as well. Having a large number of tumors of 10 and above, despite all being inside the liver, is a negative prognostic factor. Citation Format: Amichai Berkovitz, Rachael D. Migler, Adam Qureshi, Roger Vaughan, Erin L. Marcotte, Sanford M. Simon. Clinical and demographic predictors of survival for fibrolamellar hepatocellular carcinoma patients - A patient-community registry-based study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2495.
Abstract 6181: Cell line panel with HIBIT tagged endogenous proteins to accelerate PROTAC drug discovery
Authors: Yunpeng Zhai, Ming Tan, Defu Liu, Guoqian Wang, Jinying Ning, Feng Hao
Journal: Cancer Research (2022)

Abstract Recent years have seen great advancement of targeted protein degradation technology, in particular, proteolysis targeting chimeras (PROTACs) are now widely used in developing therapeutics for treating cancer. A PROTAC is a heterobifunctional small molecule with three distinct moieties: a ligand to bind a targeted protein of interest (POI), a second ligand to recruit E3 ubiquitin ligase to form a ternary complex, and a linker for bridging the two ligands. Through the E3 ubiquitin ligase pathway, properly designed PROTACs can effectively degrade POIs with high specificity, which can be pathogenic proteins, thus regulate related pathways and inhibit tumor growth. Currently, there is no high-throughput biochemical assay to measure the POI degradation in vitro, hindering the application of the PROTAC technology. Here we report the development of a high-throughput cell based assay to quantitatively measure the endogenous drug target degradation induced by PROTACs. This assay encompasses over 800 cancer cell lines, many of which are CRISPR-engineered ones on common drug targets. A unique feature of our assay is the incorporation of HiBiT short sequence tags on either N-terminal or C-terminal of endogenous protein in E3 ligase matched cell line through site-specific gene homologous recombination technology. By highly specific and sensitive detection of HiBiT tag content in cell lysates with biochemical assay, we can determine target protein degradation by PROTAC treatment. We demonstrate the utility of the assay on a wide array of drug targets including RAS, LDHA, BTK and HPK1, and show that it can accelerate PROTAC drug discovery. Citation Format: Yunpeng Zhai, Ming Tan, Defu Liu, Guoqian Wang, Jinying Ning, Feng Hao. Cell line panel with HIBIT tagged endogenous proteins to accelerate PROTAC drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6181.
Abstract 5128: Identification and characterization of nasopharyngeal carcinoma prognostic subtypes based on a circRNA classifier: Implications of stratified treatment
Authors: Yelin Liang, Yuheng Zhao, Qian Li, Wei Jiang, Jun Ma, Na Liu, Yingqin Li
Journal: Cancer Research (2022)

Abstract Accurate risk stratification for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) is crucial for treatment decisions and prognosis. Here, we introduce a circRNA-based classifier that could improve the prognostic stratification of LA-NPC patients. The circRNAs are identified by microarray profiling, followed by qRT-PCR validation and selection using a machine learning method in the training cohort (n = 170). Based on the proposed classifier, two prognostic-distinctive NPC subtypes are identified, namely the high-risk subtype (subtype H) and low-risk subtype (subtype L), which have significantly different disease-free survival (HR 2.99, 95% CI 1.58-5.67, P &amp;lt; 0.001). Validation in the internal cohort (n = 170) and external cohort (n = 150) yield similar results and the circRNA-based classifier is an independent risk factor of posttreatment relapse. Meanwhile, multiple interdependent features of different subtypes are observed, including relatively higher immune cell infiltration and immune-related pathways activation in subtype L; and predominant stromal, immunosuppressive and tumor-promoting components with moderate immune activation in subtype H. With a less aggressive and more immune-active tumor microenvironment, patients of subtype L could benefit from the addition of induction chemotherapy. In contrast, patients of subtype H, who are vulnerable to chemoresistance, display a strong tendency to benefit from additional immunotherapy. Overall, we define two NPC prognostic subtypes based on a circRNA classifier across multiple cohorts, which exhibit distinct biological ecosystems and suggest opportunities for the personalization of therapeutic regimens. Citation Format: Yelin Liang, Yuheng Zhao, Qian Li, Wei Jiang, Jun Ma, Na Liu, Yingqin Li. Identification and characterization of nasopharyngeal carcinoma prognostic subtypes based on a circRNA classifier: Implications of stratified treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5128.
Rationally designed bioactive milk-derived protein scaffolds enhanced new bone formation
Authors: Min Suk Lee, Jin Jeon, Sihyeon Park, Juhan Lim, Hee Seok Yang
Journal: Bioactive Materials (2022)

Recently, a number of studies reported that casein was composed of various multifunctional bioactive peptides such as casein phosphopeptide and β-casochemotide-1 that bind calcium ions and induce macrophage chemotaxis, which is crucial for bone homeostasis and bone fracture repair by cytokines secreted in the process. We hypothesized that the effects of the multifunctional biopeptides in casein would contribute to improving bone regeneration. Thus, we designed a tissue engineering platform that consisted of casein and polyvinyl alcohol, which was a physical-crosslinked scaffold (milk-derived protein; MDP), via simple freeze-thaw cycles and performed surface modification using 3,4-dihydroxy-l-phenylalanine (DOPA), a mussel adhesive protein, for immobilizing adhesive proteins and cytokines for recruiting cells in vivo (MDP-DOPA). Both the MDP and MDP-DOPA groups proved indirectly contribution of macrophages migration as RAW 264.7 cells were highly migrated toward materials by contained bioactive peptides. We implanted MDP and MDP-DOPA in a mouse calvarial defect orthotopic model and evaluated whether MDP-DOPA showed much faster mineral deposition and higher bone density than that of the no-treatment and MDP groups. The MDP-DOPA group showed the accumulation of host M2 macrophages and mesenchymal stem cells (MSCs) around the scaffold, whereas MDP presented mostly M1 macrophages in the early stage.
Abstract 1942: Interpretation of machine learning methods for the prediction of breast and prostate cancer risk
Authors: Adam Klie, James Talwar, Meghana Pagadala, Hannah Carter
Journal: Cancer Research (2022)

Abstract Neural networks are powerful tools for modeling genetic contributions to cancer risk that can theoretically capture nonlinear, epistatic interactions between disease-associated loci in heritable cancers. Recent studies applying neural networks and other machine learning methods to complex trait risk prediction from single nucleotide polymorphism (SNP) array data have shown promise in improving risk stratification. However, current performance gains for neural networks when compared to traditional polygenic risk scoring (PRS) approaches and other nonlinear and linear machine learning methods have been modest. Moreover, there remains substantial debate as to the effect of capturing epistatic interactions between SNPs in risk modeling. Central to the debate has been the difficulty in interpreting the complex, nonlinear mapping learned by neural networks and other nonlinear modeling approaches. To decipher the importance of capturing nonlinear interactions in cancer risk modeling, we first applied several PRS approaches to the prediction of breast and prostate cancer status for individuals in the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) and Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) datasets respectively. Consistent with previous studies of complex disease prediction using machine learning, we noted greater predictive capability upon inclusion of more loci in our modeling but only small performance gains when nonlinearity was captured in both cancer types. We then applied machine learning interpretation methods to derive a score for each variant per method, including several neural network interpretation methods which, to our knowledge, have not been applied in this context. We noted varying degrees of concordance between the scores assigned by each method. Finally, we performed pairwise in silico perturbations on salient features and techniques from network biology to identify epistatic interactions between loci captured by each model. Our work represents a comprehensive study of methods for inferring both variant level and epistatic interaction contributions to cancer risk. Citation Format: Adam Klie, James Talwar, Meghana Pagadala, Hannah Carter. Interpretation of machine learning methods for the prediction of breast and prostate cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1942.
Abstract 675: Facilitating G-quadruplex formation in the KRAS promoter with polypurine reverse Hoogsteen oligonucleotides
Authors: Alexandra Maria Psaras, Simonas Valiuska, Veronique Noe, Carlos J. Ciudad, Tracy A. Brooks
Journal: Cancer Research (2022)

Abstract KRAS is a GTPase involved in the proliferation signaling of a number of growth factors, such as epidermal growth factor. The protein is mutated or upregulated in an array of cancers, including pancreatic and ovarian cancers, where it correlates with more aggressive and chemoresistant disease. Within the promoter of KRAS lies a G-rich region capable of forming the higher order non-canonical DNA structure, the G-quadruplex (G4). Stabilization of G4 formation in the mid-region of the KRAS promoter downregulates transcription and facilitates decreased growth and chemo-sensitization of pancreatic and ovarian cancer cells with aberrant KRAS signaling. Our collaborative team designed Polypurine Reverse Hoogsteen (PPRH) hairpin oligonucleotides that establish Watson Crick bonds with the pyrimidine strand within the KRAS-mid-G4-forming region to enhance G4 formation, downregulate KRAS transcription and mediate an anti-proliferative effect. In particular, two PPRHs were designed to interact with the 3’ and 5’ ends of the G4-forming region, along with two correlating W:C, and one scramble, controls. The binding of these oligonucleotides to the G4-forming region was verified by gel electrophoresis, and the cell activity was examined in vitro both by luciferase and in pancreatic and ovarian cancer cells. Using a luciferase construct driven by the KRAS promoter, only the PPRHs, and none of the control oligonucleotides, significantly decreased activity. Cytotoxicity experiments in KRAS dependent and independent cell lines demonstrated that PPRHs, but not control oligonucleotides, selectively suppressed proliferation only in the dependent pancreatic and ovarian cancer cell lines. Correlation of the cytotoxic effects of these potential therapeutic PPRHs with transcriptional downregulation is under investigation. PPRH also demonstrated synergistic activity with a KRAS promoter selective G4-stabilizing compound in KRAS-dependent pancreatic cells, and sensitization to standard chemotherapeutic regimens is also being studied. These designed PPRH oligonucleotides selectively stabilize G4 formation within the KRAS mid promoter region, and represent an innovative approach both for G4-stabilization and KRAS modulation with potential for development into novel therapeutics. Citation Format: Alexandra Maria Psaras, Simonas Valiuska, Veronique Noe, Carlos J. Ciudad, Tracy A. Brooks. Facilitating G-quadruplex formation in the KRAS promoter with polypurine reverse Hoogsteen oligonucleotides [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 675.